The molecular mechanisms whereby atypical neuroleptic (AN) differ from typical neuroleptics (TN) remain elusive. [F18]-2-fluoro-2-deoxy-D- glucose (FDG) with positron emission tomography (PET) was used to determine whether pretreatment functional patterns of metabolic activity of schizophrenic patients while performing an auditory discrimination task (CPT) predicted response to the TN fluphenazine and the AN clozapine. Abnormally lower metabolic rates in the right anterior midprefrontal cortex predicted a better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role n the expression of psychotic symptoms and the mediation of response to antipsychotics. While dopamine pathway abnormalities have been suspected in both Tourettes Syndrome (TS) and in Attention Deficit/Hyperactivity Disorder (ADHD) on the basis of circumstantial evidence, there has been no direct evidence for these abnormalities. [F-18]F-DOPA is PET tracer that accumulates as a result of DOPA decarboxylase activity, and therefore provides a measure of presynaptic dopamine system function. Scanning with [F-18]F-DOPA, regionally specific abnormalities in the dopamine system were found in TS (basal ganglia) and in ADHD (prefrontal cortex). The opiate and dopamine systems are believed to have significant interactions. Using bilaterally and unilaterally-MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)- lesioned rhesus monkeys and the opiate-receptor dependent tracer cyclofoxy (6-deoxy-6-beta ? [F18]fluoronaltrexone), large changes in opiate receptor avidity were observed bilaterally in the subcortex of these animals with reduced dopamine input to the basal ganglia that are used as models of Parkinson?s disease. - PET, dopamine, Alzheimer's Disease, opiates, MPTP, ADHD, Tourette's - Human Subjects